3OHF

Crystal structure of beta-site app-cleaving enzyme 1 (BACE-WT) complex with bms-655295 aka n~3~-((1s,2r)-1- benzyl-2-hydroxy-3-((3-methoxybenzyl)amino)propyl)-n~1~, n~1~-dibutyl-1h-indole-1,3-dicarboxamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.205 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Synthesis and SAR of indole-and 7-azaindole-1,3-dicarboxamide hydroxyethylamine inhibitors of BACE-1.

Marcin, L.R.Higgins, M.A.Zusi, F.C.Zhang, Y.Dee, M.F.Parker, M.F.Muckelbauer, J.K.Camac, D.M.Morin, P.E.Ramamurthy, V.Tebben, A.J.Lentz, K.A.Grace, J.E.Marcinkeviciene, J.A.Kopcho, L.M.Burton, C.R.Barten, D.M.Toyn, J.H.Meredith, J.E.Albright, C.F.Bronson, J.J.Macor, J.E.Thompson, L.A.

(2011) Bioorg Med Chem Lett 21: 537-541

  • DOI: https://doi.org/10.1016/j.bmcl.2010.10.079
  • Primary Citation of Related Structures:  
    3OHF, 3OHH

  • PubMed Abstract: 

    Heterocyclic replacement of the isophthalamide phenyl ring in hydroxyethylamine (HEA) BACE-1 inhibitors was explored. A variety of indole-1,3-dicarboxamide HEAs exhibited potent BACE-1 enzyme inhibition, but displayed poor cellular activity. Improvements in cellular activity and aspartic protease selectivity were observed for 7-azaindole-1,3-dicarboxamide HEAs. A methylprolinol-bearing derivative (10n) demonstrated robust reductions in rat plasma Aβ levels, but did not lower rat brain Aβ due to poor central exposure. The same analog exhibited a high efflux ratio in a bidirectional Caco-2 assay and was likely a substrate of the efflux transporter P-glycoprotein. X-ray crystal structures are reported for two indole HEAs in complex with BACE-1.


  • Organizational Affiliation

    Bristol-Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA. lawrence.marcin@bms.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B
455Homo sapiensMutation(s): 0 
Gene Names: BACEBACE1KIAA1149
EC: 3.4.23.46
UniProt & NIH Common Fund Data Resources
Find proteins for P56817 (Homo sapiens)
Explore P56817 
Go to UniProtKB:  P56817
PHAROS:  P56817
GTEx:  ENSG00000186318 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP56817
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
3HF Binding MOAD:  3OHF IC50: 94 (nM) from 1 assay(s)
PDBBind:  3OHF IC50: 94 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.205 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 88.982α = 90
b = 130.233β = 90
c = 86.596γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-04-06
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-03-01
    Changes: Database references